Targeting Tregs in Malignant Brain Cancer: Overcoming IDO.
Targeting Tregs in Malignant Brain Cancer: Overcoming IDO.
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DOI：
10.3389/fimmu.2013.00116
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发表时间：
2013
影响因子：
7.3
通讯作者：
Lesniak MS
中科院分区：
文献类型：
--
作者：
Wainwright DA;Dey M;Chang A;Lesniak MS
多形性胶质母细胞瘤（GBM）是最常见的成人原发性脑肿瘤，预后非常差，其标志性特征之一是CD4+CD25+Foxp3+调节性T细胞（Tregs）的积累。调节性T细胞（Tregs）主要分为两类：由未成熟T细胞与胸腺上皮基质细胞相互作用产生的胸腺源性天然Tregs (nTregs)，以及由CD4+FoxP3−T细胞转化为表达FoxP3的细胞产生的诱导性Tregs （iTregs）。通常，这些Treg亚群通过维持自身抗原的耐受性来相互补充，从而抑制自身免疫，同时也对非自身抗原产生有效的免疫反应，从而促进感染保护。然而，Tregs也被证明与促进病理结果（包括癌症）有关。在GBM的情况下，nTregs似乎是导致免疫治疗失败的主要因素，最终导致肿瘤进展。一些针对这些细胞的治疗尝试取得了不同程度的成功。血脑屏障穿越化疗药物，替莫唑胺和环磷酰胺（CTX），针对Treg转录调节因子FoxP3的疫苗接种，以及针对Treg相关细胞表面分子CD25、CTLA-4和GITR的单克隆抗体都是正在研究的不同治疗方法。过去的方法不太成功的原因是吲哚胺2,3-双加氧酶1 （IDO）的表达，这是一种在GBM中过度表达的色氨酸分解代谢酶，并在调节肿瘤浸润性Treg水平中起关键作用。在此，我们回顾了目前关于脑癌Tregs的文献，提供了详细的表型，发病机制的致病机制，以及针对这一人群的治疗策略。
One of the hallmark features of glioblastoma multiforme (GBM), the most common adult primary brain tumor with a very dismal prognosis, is the accumulation of CD4+CD25+Foxp3+ regulatory T cells (Tregs). Regulatory T cells (Tregs) segregate into two primary categories: thymus-derived natural Tregs (nTregs) that develop from the interaction between immature T cells and thymic epithelial stromal cells, and inducible Tregs (iTregs) that arise from the conversion of CD4+FoxP3− T cells into FoxP3 expressing cells. Normally, these Treg subsets complement one another’s actions by maintaining tolerance of self-antigens, thereby suppressing autoimmunity, while also enabling effective immune responses toward non-self-antigens, thus promoting infectious protection. However, Tregs have also been shown to be associated with the promotion of pathological outcomes, including cancer. In the setting of GBM, nTregs appear to be primary players that contribute to immunotherapeutic failure, ultimately leading to tumor progression. Several attempts have been made to therapeutically target these cells with variable levels of success. The blood brain barrier-crossing chemotherapeutics, temozolomide, and cyclophosphamide (CTX), vaccination against the Treg transcriptional regulator, FoxP3, as well as mAbs against Treg-associated cell surface molecules CD25, CTLA-4, and GITR are all different therapeutic approaches under investigation. Contributing to the poor success of past approaches is the expression of indoleamine 2,3-dioxygenase 1 (IDO), a tryptophan catabolizing enzyme overexpressed in GBM, and critically involved in regulating tumor-infiltrating Treg levels. Herein, we review the current literature on Tregs in brain cancer, providing a detailed phenotype, causative mechanisms involved in their pathogenesis, and strategies that have been used to target this population, therapeutically.